2-Methylene-19-nor-20(S)-1alpha-hydroxy-bis-homo-pregnacalciferol in crystalline form

ABSTRACT

A method of purifying 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacaciferol to obtain 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol in crystalline form. The method includes the steps of boiling a solvent such as acetone under inert atmosphere, dissolving a product containing 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol to be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol crystals, and recovering the 2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol crystals.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is based on and claims priority from U.S.Provisional Patent Application No. 60/341,138 filed Dec. 13, 2001.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to purification of organiccompounds, and more particularly to the purification of2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol (referredto herein as 2MBP and/or 2-MbisP) by preparing it in crystalline form.

[0003] Purification of organic compounds, especially those designatedfor pharmaceutical use, is of considerable importance for chemistssynthesizing such compounds. Preparation of the compound usuallyrequires many synthetic steps and, therefore, the final product can becontaminated not only with side-products derived from the last syntheticstep of the procedure but also with compounds that were formed inprevious steps. Even chromatographic purification, which is a veryefficient but relatively time-consuming process, does not usuallyprovide compounds which are sufficiently pure to be used as drugs.

[0004] Depending on the method used to synthesize 1α-hydroxyvitamin Dcompounds, different minor undesirable compounds can accompany the finalproduct. Thus, for example, if direct C-1 hydroxylation of 5,6-transgeometric isomer of vitamin D is performed, followed by SeO₂/NMOoxidation and photochemical irradiation [see Andrews et al., J. Org.Chem. 51, 1635 (1986); Calverley et al., Tetrahedron 43, 4609 (1987);Choudry et al., J. Org. Chem. 58, 1496 (1993)], the final1α-hydroxyvitamin D product can be contaminated with 1β-hydroxy- as wellas 5,6-trans isomers. If the method consists of C-1 allylic oxidation ofthe 4-phenyl-1,2,4-triazoline-3,5-dione adduct of the previtamin Dcompound, followed by cycloreversion of the modified adduct under basicconditions [Nevinckx et al., Tetrahedron 47, 9419 (1991); Vanmaele etal., Tetrahedron 41, 141 (1985) and 40, 1179 (1991); Vanmaele et al.,Tetrahedron Lett. 23, 995 (1982)], one can expect that the desired1α-hydroxyvitamin can be contaminated with the previtamin5(10),6,8-triene and 1β-hydroxy isomer. One of the most useful C-1hydroxylation methods, of very broad scope and numerous applications, isthe experimentally simple procedure elaborated by Paaren et al. [see J.Org. Chem. 45, 3253 (1980) and Proc. Natl. Acad. Sci. U.S.A. 75, 2080(1978)]. This method consists of allylic oxidation of 3,5-cyclovitamin Dderivatives, readily obtained from the buffered solvolysis of vitamin Dtosylates, with SeO₂/t-BuOOH and subsequent acid-catalyzedcycloreversion to the desired 1α-hydroxy compounds. Taking into accountthis synthetic path it is reasonable to assume that the final productcan be contaminated with 1α-hydroxy epimer, 5,6-trans isomer and theprevitamin D form. 1α-hydroxyvitamin D₄ is another undesirablecontaminant found in 1α-hydroxyvitamin D compounds synthesized fromvitamin D₂ or from ergosterol. 1α-hydroxyvitamin D₄ results from C-1oxidation of vitamin D₄, which in turn is derived from contamination ofthe commercial ergosterol material. Typically, the final product maycontain up to about 1.5% by weight 1α-hydroxyvitamin D₄. Thus, apurification technique that would eliminate or substantially reduce theamount of 1α-hydroxyvitamin D₄ in the final product to less than about01.-0.2% would be highly desirable.

[0005] The vitamin D conjugated triene system is not only heat- andlight-sensitive but it is also prone to oxidation, leading to thecomplex mixture of very polar compounds. Oxidation usually happens whena vitamin D compound has been stored for a prolonged time. Other typesof processes that can lead to a partial decomposition of vitamin Dcompounds consist of the some water-elimination reactions; their drivingforce is allylic (1α) and homoallylic (3β-) position of the hydroxygroups. The presence of such above-mentioned oxidation and eliminationproducts can be easily detected by thin-layer chromatography. Thus, forexample, using precoated aluminum silica sheets [with UV indicator; fromEM Science (Cherry Hill, N.J.)] and solvent system hexane-ethyl acetate(4:6), the spot of 1α-OH-D₂ (R_(f) 0.27) and its elimination products(R_(f)'s ca. 0.7-0.9) are visible in ultraviolet light. Also, afterspraying with sulfuric acid and heating, an additional spot can bevisualized (R_(f) 0), derived from oxidation products.

[0006] Usually, all 1α-hydroxylation procedures require at least onechromatographic purification. However, even chromatographically purified1α-hydroxyvitamin D compounds, although showing consistent spectroscopicdata, suggesting homogeneity, does not meet the purity criteria requiredfor therapeutic agents that can be orally, parenterally or transdermallyadministered. Therefore, it was evident that a suitable method ofpurification of 2MBP is required.

SUMMARY OF THE INVENTION

[0007] The present invention relates to a method of purifying 2MBP bymeans of crystallization to obtain 2MBP in crystalline form. The solventplays a crucial role in the crystallization process, and is typically anindividual liquid substance or a suitable mixture of different liquids.For crystallizing 2MBP, the most appropriate solvent and/or solventsystem is characterized by the following factors:

[0008] (1) low toxicity;

[0009] (2) low boiling point;

[0010] (3) significant dependence of solubility properties with regardto temperature (condition necessary for providing satisfactorycrystallization yield); and

[0011] (4) relatively low cost.

[0012] It was found that highly apolar solvents (e.g. hydrocarbons) werenot suitable due to the low solubility of 2MBP in them. Quite thereverse situation occurred in highly polar solvent media (e.g.alcohols), in which 2MBP showed too high solubility. Therefore, it wasconcluded that for the successful crystallization of 2MBP, a solvent ofmedium polarity is required. Interestingly, hexane, so frequently usedfor crystallization purposes, was found less suitable forcrystallization of 2MBP. However, it was found that an individualsolvent, namely acetone, was most useful for the crystallization of2MBP. In addition, it is believed that solvent systems utilizing ethylacetate, or isopropanol, or chloroform, or dichloromethane, or diethylether would also perform well. These solvents are all very easy toremove by evaporation or other well known methods. In all cases thecrystallization process occurred easily and efficiently; and theprecipitated crystals were sufficiently large to assure their recoveryby filtration.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1 is an illustration of the three dimensional structure of2MBD as defined by the atomic positional parameters discovered and setforth herein.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention provides2-methylene-19-nor-20(S)-1α-hydroxy-bis-homo-pregnacalciferol (2MBP) incrystalline form, a pharmacologically important compound, characterizedby the formula shown below:

[0015] The present invention also provides a valuable method ofpurification of 2MBP. The purification technique involves obtaining the2MBP product in crystalline form by utilizing a crystallizationprocedure wherein the 2MBP material to be purified is dissolved using asthe solvent a single solvent system comprised of acetone, ethyl acetate,isopropanol, chloroform, dichloromethane, or diethyl ether. Thepreferred solvent is acetone. Thereafter, the solvent can be removed byevaporation, with or without vacuum, or other means as is well known.The technique can be used to purify a wide range of final productscontaining 2MBP obtained from any known synthesis thereof, and invarying concentrations, i.e. from microgram amounts to kilogram amounts.As is well known to those skilled in this art, the amount of solventutilized should be minimized and/or adjusted according to the amount of2MBP to be purified.

[0016] The usefulness and advantages of the present crystallizationprocedures is shown in the following specific Examples 1 and 2. Aftercrystallization, the precipitated material was observed under amicroscope to confirm its crystalline form. Additionally, X-raydiffraction analysis was performed. Yields of crystallizations were highand the obtained crystals showed a relatively sharp melting point of162-164° C.

[0017] The described crystallization process of the synthetic 2MBPproduct represents a valuable purification method, which can remove notonly some side products derived from the synthetic path, but, moreover,concomitant 1α-hydroxyvitamin D₄. Such impurity is the result of thecontamination of natural ergosterol with its 22,23-dihydro analog.

CRYSTALLIZATION OF 2MBP EXAMPLE 1 Crystallization From Acetone

[0018] (a) 2MBP product to be purified may be dissolved in boilingacetone (1.2 mL, Aldrich) under argon atmosphere, left at roomtemperature (68° F.) for a few hours (1-3 hrs) and then in arefrigerator (35-45° F.) overnight (8-12 hrs). The precipitated crystalsshould be filtered off, washed with a small volume of a cold (0° C.)acetone and dried.

[0019] (b) These crystals of 2MBP may then be recrystallized withacetone (0.5 mL) as described in Example 1(a). The precipitated crystalshave a relatively sharp melting point of 162-164° C., and were observedunder a microscope to confirm their crystalline form.

EXAMPLE 2 Experimental

[0020] A colorless plate-shaped crystal of dimensions 0.40×0.25×0.03 mmwas utilized for the structural analysis. Intensity data were collectedwith a Siemens HISTAR area detector mounted on a platform goniometerusing Cu Kα radiation (λ=1.54178 Å) focused with Goebel optics. Thecrystal was mounted on a thin nylon fiber with vacuum grease and datawere collected at ambient temperature, 293° K. The intensity data weremeasured as a series of ω oscillation frames each of 0.25°; these werecomprised of 5 scans (500 images each, 40 sec./image) at detector 2θ of−85° and 2 scans (500 images each, 20 sec./image) at detector 2Θ of−40°. The detector was operated in 512×512 mode and was positioned 6.0cm from the sample. Coverage of unique data was 95.4% complete to 58.88degrees in θ. The first 50 frames were repeated at the end of datacollection and showed essentially no decay of the crystal diffractionduring the data collection. A total of 6917 data was measured in therange 4.38<θ58.88°. The data were merged and scaled to form a set of2697 independent data with R(int)=0.0562 using SAINT (Bruker-AXS, Inc.).

[0021] The orthorhombic space group P2(1)2(1)2(1) was determined bysystematic absences and statistical tests and verified by subsequentrefinement. The structure was solved by direct methods and refined byfull-matrix least-squares methods on F² using SHELXL-97 (G. M.Sheldrick, 1994; SHELXTL Version 5 Reference Manual, Bruker-AXS, Inc.).Hydrogen atom positions were intially located in Fourier differencemaps, but refined by a riding model with idealized geometries.Non-hydrogen atoms were refined with anisotropic displacementparameters. A total of 229 parameters were refined against 0 restraintsand 2697 data to give wR(F²)=0.1369 and S=1.088 for weights ofw=I/[s²(F²)+(0.0824 P)²], where P=[F_(o) ²+2F_(c) ²]/3. The final R(F)was 0.0544 for the 2697 observed, [F>2s(F)], data. The final differencemap had maxima and minima of 0.126 and −0.153 e/Å³, respectively.

[0022] The three dimensional structure of 2MBP as defined by thefollowing physical data and atomic positional parameters described andcalculated herein is illustrated in FIG. 1. TABLE 1 Crystal data andstructure refinement for 2-MbisP. Empirical formula C23 H36 O2 Formulaweight 344.52 Temperature 293(2) K Wavelength 1.54178 Å Crystal system,space group Orthorhombic, P2(1)2(1)2(1) Unit cell dimensions a =6.6320(13) Å α = 90° b = 15.514(3) Å β = 90° c = 20.194(4) Å γ = 90°Volume 2077.7(7) Å³ Z, Calculated density 4, 1.101 Mg/m³ Absorptioncoefficient 0.520 mm⁻¹ F(000) 760 Crystal size 0.40 × 0.25 × 0.03 mmTheta range for data collection 4.38 to 58.88° Limiting indices −7 <= h<= 5, −12 <= k <= 17, −22 <= 1 <= 21 Reflections collected/unique6917/2697 [R_(int) = 0.0562] Completeness to theta = 25.00 95.4%Refinement method Full-matrix least-squares on F²Data/restraints/parameters 2697/0/229 Goodness-of-fit on F² 1.088 FinalR indices [I > 2sigma(I)] R1 = 0.0544, wR2 = 0.1369 R indices (all data)R1 = 0.0622, wR2 = 0.1453 Largest diff. peak and hole 0.126 and −0.153e/A⁻³

[0023] TABLE 2 Atomic coordinates (× 10⁴) and equivalent isotropicdisplacement parameters (Å² × 10³) for 2-MbisP. U(eq) is defined as onethird of the trace of the orthogonalized Uij tensor. x y z U(eq) O(1) 1842(3) 3525(1) 5011(1)  62(1) O(3)  7954(4) 3113(1) 4476(2)  78(1)C(1)  3883(5) 3729(2) 4852(2)  50(1) C(2)  4569(5) 3359(2) 4201(2) 58(1) C(3)  6698(5) 3569(2) 4030(2)  61(1) C(4)  7074(6) 4537(2)4057(2)  59(1) C(5)  6301(5) 4937(2) 4686(2)  48(1) C(6)  7497(5)5433(2) 5059(2)  52(1) C(7)  7012(5) 5872(2) 5673(2)  53(1) C(8) 8248(5) 6371(2) 6020(2)  50(1) C(9) 10390(5) 6589(2) 5828(2)  65(1)C(10)  4161(5) 4704(2) 4851(2)  51(1) C(11) 10739(6) 7562(2) 5809(2) 70(1) C(12) 10108(6) 8006(2) 6452(2)  61(1) C(13)  7933(5) 7806(2)6640(1)  47(1) C(14)  7696(5) 6814(2) 6661(2)  50(1) C(15)  5663(6)6668(2) 6982(2)  62(1) C(16)  5453(5) 7416(2) 7474(2)  59(1) C(17) 7251(5) 8038(2) 7353(2)  51(1) C(18)  6466(6) 8205(2) 6135(2)  64(1)C(19)  3405(7) 2898(3) 3811(2)  97(2) C(20)  6703(6) 8967(2) 7542(2) 65(1) C(21)  6012(8) 9017(3) 8269(2)  92(2) C(22)  8368(7) 9636(2)7418(2)  89(1) C(23) 10284(9) 9512(3) 7809(3) 116(2)

[0024] TABLE 3 Bond lengths [Å] and angles [°] for 2-MbisP. O(1)-C(1)1.426(4) O(3)-C(3) 1.416(4) C(1)-C(2) 1.505(5) C(1)-C(10) 1.524(4)C(2)-C(19) 1.314(5) C(2)-C(3) 1.490(5) C(3)-C(4) 1.522(4) C(4)-C(5)1.504(5) C(5)-C(6) 1.335(4) C(5)-C(10) 1.502(5) C(6)-C(7) 1.452(4)C(7)-C(8) 1.327(4) C(8)-C(9) 1.511(5) C(8)-C(14) 1.511(4) C(9)-C(11)1.527(5) C(11)-C(12) 1.530(5) C(12)-C(13) 1.523(5) C(13)-C(18) 1.539(5)C(13)-C(14) 1.548(4) C(13)-C(17) 1.553(4) C(14)-C(15) 1.513(5)C(15)-C(16) 1.534(5) C(16)-C(17) 1.553(5) C(17)-C(20) 1.535(5)C(20)-C(22) 1.536(6) C(20)-C(21) 1.540(5) C(22)-C(23) 1.508(7)O(1)-C(1)-C(2) 113.5(2) O(1)-C(1)-C(10) 109.6(2) C(2)-C(1)-C(10)109.9(3) C(19)-C(2)-C(3) 122.5(3) C(19)-C(2)-C(1) 123.6(3)C(3)-C(2)-C(1) 113.9(3) O(3)-C(3)-C(2) 107.5(3) O(3)-C(3)-C(4) 111.9(3)C(2)-C(3)-C(4) 111.3(3) C(5)-C(4)-C(3) 112.5(3) C(6)-C(5)-C(10) 125.1(3)C(6)-C(5)-C(4) 120.7(3) C(10)-C(5)-C(4) 114.2(3) C(5)-C(6)-C(7) 128.3(3)C(8)-C(7)-C(6) 126.0(3) C(7)-C(8)-C(9) 125.1(3) C(7)-C(8)-C(14) 124.6(3)C(9)-C(8)-C(14) 110.3(3) C(8)-C(9)-C(11) 111.7(3) C(5)-C(10)-C(1)110.8(2) C(9)-C(11)-C(12) 112.5(3) C(13)-C(12)-C(11) 112.2(3)C(12)-C(13)-C(18) 110.6(3) C(12)-C(13)-C(14) 107.8(3) C(18)-C(13)-C(14)110.8(3) C(12)-C(13)-C(17) 117.3(3) C(18)-C(13)-C(17) 109.7(3)C(14)-C(13)-C(17) 100.1(2) C(15)-C(14)-C(8) 121.0(3) C(15)-C(14)-C(13)104.6(3) C(8)-C(14)-C(13) 113.8(2) C(14)-C(15)-C(16) 104.2(3)C(15)-C(16)-C(17) 107.4(3) C(20)-C(17)-C(16) 111.3(3) C(20)-C(17)-C(13)121.2(3) C(16)-C(17)-C(13) 103.0(2) C(22)-C(20)-C(17) 115.0(3)C(22)-C(20)-C(21) 1.09.6(3) C(17)-C(20)-C(21) 110.8(3) C(23)-C(22)-C(20)115.7(4)

[0025] TABLE 4 Anisotropic displacement parameters (Å² × 10³) for2-MbisP. The anisotropic displacement factor exponent takes the form:−2π²[h² a*² U11 + . . . + 2 h k a* b* U12] U11 U22 U33 U23 U13 U12 O(1)36(1) 59(1) 92(2)  −7(1)  −3(1)  −5(1) O(3) 42(1) 48(1) 145(2)     3(1)−17(2)    2(1) C(1) 34(2) 45(2) 70(2)  −5(2) −11(2)  −1(1) C(2) 39(2)51(2) 83(2) −21(2) −14(2)    6(1) C(3) 55(2) 52(2) 75(2) −19(2)  −7(2)   8(2) C(4) 60(2) 56(2) 61(2)  −2(2)    2(2)    0(2) C(5) 52(2) 34(1)58(2)    3(1)  −5(2)    1(1) C(6) 51(2) 45(2) 61(2)    2(1)    5(2) −9(2) C(7) 56(2) 42(2) 62(2)    2(1)    6(2)  −8(2) C(8) 47(2) 44(2)58(2)    3(1)  −1(2) −10(2) C(9) 48(2) 75(2) 73(2) −15(2)    3(2) −12(2)C(10) 44(2) 41(2) 66(2) −11(1)  −6(2)    4(1) C(11) 59(2) 78(2) 72(2)−12(2)   11(2) −32(2) C(12) 59(2) 61(2) 63(2)  −5(2)    1(2) −22(2)C(13) 43(2) 51(2) 47(2)    5(1)  −6(2)  −7(2) C(14) 45(2) 52(2) 53(2)   4(1)  −4(2)  −8(2) C(15) 53(2) 64(2) 69(2)    1(2)    9(2) −19(2)C(16) 48(2) 71(2) 58(2)    3(2)    4(2)    0(2) C(17) 49(2) 53(2) 50(2)   1(1)  −7(2)  −1(2) C(18) 71(3) 66(2) 57(2)   10(2) −11(2)  −5(2)C(19) 53(3) 122(4)  117(3)  −68(3)  −9(3)  −8(2) C(20) 73(3) 59(2) 64(2) −5(2)  −2(2)    8(2) C(21) 117(4)  82(3) 76(2) −16(2)   20(3)    9(3)C(22) 104(4)  63(2) 99(3) −12(2)   18(3)  −6(2) C(23) 107(4)  101(4) 140(5)  −39(3)  −4(4) −25(3)

[0026] TABLE 5 Hydrogen coordinates (× 10⁴) and isotropic displacementparameters (Å² × 10³) for 2-MbisP. x y z U(eq) H(1O) 2030 2820 5188 75H(3O) 9248 3381 4573 94 H(1) 4744 3489 5201 60 H(3) 6972 3366 3580 73H(4A) 8510 4644 4021 71 H(4B) 6418 4808 3682 71 H(6) 8807 5506 4904 63H(7) 5716 5796 5840 64 H(9A) 10678 6347 5395 78 H(9B) 11311 6330 6144 78H(10A) 3261 4960 4528 61 H(10B) 3817 4933 5284 61 H(11A) 9979 7806 544484 H(11B) 12157 7673 5728 84 H(12A) 10992 7820 6807 74 H(12B) 10264 86246403 74 H(14) 8690 6614 6986 60 H(15A) 5627 6117 7210 74 H(15B) 45926682 6655 74 H(16A) 5482 7201 7925 71 H(16B) 4186 7714 7405 71 H(17)8337 7857 7652 61 H(18A) 6780 8804 6077 97 H(18B) 5109 8148 6295 97H(18C) 6593 7911 5719 97 H(19A) 3904 2689 3412 117 H(19B) 2083 2780 3935117 H(20) 5547 9133 7268 78 H(21A) 7037 8779 8551 138 H(21B) 4785 86978323 138 H(21C) 5783 9609 8388 138 H(22A) 8703 9627 6950 106 H(22B) 783210203 7518 106 H(23A) 9974 9502 8273 174 H(23B) 11194 9978 7717 174H(23C) 10902 8976 7684 174

[0027] TABLE 6 Torsion angles [°] for 2-MbisP. O(1)-C(1)-C(2)-C(19)0.5(5) C(10)-C(1)-C(2)-C(19) −122.6(4) O(1)-C(1)-C(2)-C(3) 179.9(3)C(10)-C(1)-C(2)-C(3) 56.8(3) C(19)-C(2)-C(3)-O(3) −111.3(4)C(1)-C(2)-C(3)-O(3) 69.2(3) C(19)-C(2)-C(3)-C(4) 125.8(4)C(1)-C(2)-C(3)-C(4) −53.7(4) O(3)-C(3)-C(4)-C(5) −71.4(4)C(2)-C(3)-C(4)-C(5) 48.9(4) C(3)-C(4)-C(5)-C(6) 128.0(3)C(3)-C(4)-C(5)-C(10) −50.1(4) C(10)-C(5)-C(6)-C(7) −2.4(5)C(4)-C(5)-C(6)-C(7) 179.7(3) C(5)-C(6)-C(7)-C(8) −178.8(3)C(6)-C(7)-C(8)-C(9) 1.4(5) C(6)-C(7)-C(8)-C(14) −179.6(3)C(7)-C(8)-C(9)-C(11) 125.7(3) C(14)-C(8)-C(9)-C(11) −53.4(4)C(6)-C(5)-C(10)-C(1) −125.0(3) C(4)-C(5)-C(10)-C(1) 53.1(3)O(1)-C(1)-C(10)-C(5) 179.9(2) C(2)-C(1)-C(10)-C(5) −54.7(3)C(8)-C(9)-C(11)-C(12) 53.0(4) C(9)-C(11)-C(12)- −54.6(4)C(11)-C(12)-C(13)-C(18) −66.8(4) C(13) C(11)-C(12)-C(13)- 54.5(4)C(11)-C(12)-C(13)-C(17) 166.4(3) C(14) C(7)-C(8)-C(14)-C(15) 3.9(5)C(9)-C(8)-C(14)-C(15) −177.0(3) C(7)-C(8)-C(14)-C(13) −122.0(3)C(9)-C(8)-C(14)-C(13) 57.2(4) C(12)-C(13)-C(14)- 168.8(3)C(18)-C(13)-C(14)-C(15) −70.1(3) C(15) C(17)-C(13)-C(14)- 45.6(3)C(12)-C(13)-C(14)-C(8) −57.1(3) C(15) C(18)-C(13)-C(14)- 64.1(4)C(17)-C(13)-C(14)-C(8) 179.7(3) C(8) C(8)-C(14)-C(15)- −163.1(3)C(13)-C(14)-C(15)-C(16) −33.1(3) C(16) C(14)-C(15)-C(16)- 7.4(4)C(15)-C(16)-C(17)-C(20) 151.9(3) C(17) C(15)-C(16)-C(17)- 20.6(3)C(12)-C(13)-C(17)-C(20) 79.2(4) C(13) C(18)-C(13)-C(17)- −48.2(4)C(14)-C(13)-C(17)-C(20) −164.7(3) C(20) C(12)-C(13)-C(17)- −155.7(3)C(18)-C(13)-C(17)-C(16) 76.9(3) C(16) C(14)-C(13)-C(17)- −39.5(3)C(16)-C(17)-C(20)-C(22) −178.0(3) C(16) C(13)-C(17)-C(20)- −56.8(5)C(16)-C(17)-C(20)-C(21) 56.9(4) C(22) C(13)-C(17)-C(20)- 178.1(3)C(17)-C(20)-C(22)-C(23) −62.9(5) C(21) C(21)-C(20)-C(22)- 62.8(5) C(23)

[0028] TABLE 7 Observed and calculated structure factors for 2-MbisP. hk l 10Fo 10Fc 10s h k l 10Fo 10Fc 10s h k l 10Fo 10Fc 10s h k l 10Fo10Fc 10s h k l 10Fo 10Fc 10s 4 0 0 51 50 3 1 15 0 43 53 3 0 6 1 298 3288 −4 14 1 38 35 5 1 5 2 153 145 7 6 0 0 48 54 4 2 15 0 82 87 2 1 6 1 326324 4 −3 14 1 54 53 3 2 5 2 175 176 2 1 1 0 108 125 1 3 15 0 53 49 3 2 61 62 70 2 −2 14 1 95 101 3 3 5 2 156 167 5 2 1 0 813 823 10 0 16 0 28 248 3 6 1 76 73 2 −1 14 1 78 78 2 4 5 2 194 188 2 4 1 0 448 435 4 1 16 025 18 5 4 6 1 68 62 1 0 14 1 73 68 1 5 5 2 99 96 2 5 1 0 62 62 1 2 16 017 12 8 5 6 1 125 129 2 1 14 1 78 79 1 6 5 2 84 79 3 6 1 0 65 72 2 1 170 54 37 10 6 6 1 89 91 2 2 14 1 97 101 2 7 5 2 70 47 4 0 2 0 650 820 8 10 1 304 297 5 −5 7 1 152 158 5 3 14 1 44 53 5 −6 6 2 65 66 3 1 2 0 510519 6 2 0 1 86 79 1 −4 7 1 168 165 1 4 14 1 44 34 5 −5 6 2 60 66 2 2 2 088 88 2 4 0 1 115 107 1 −3 7 1 138 136 2 −3 15 1 33 5 5 −4 6 2 74 77 1 42 0 217 213 2 5 0 1 111 115 2 −2 7 1 101 94 2 −2 15 1 46 46 6 −3 6 2 130128 3 5 2 0 120 117 1 6 0 1 36 28 4 −1 7 1 219 219 3 −1 15 1 25 30 6 −26 2 150 159 2 6 2 0 36 42 5 −6 1 1 56 55 3 0 7 1 223 236 2 0 15 1 38 302 −1 6 2 233 248 3 7 2 0 37 49 7 −5 1 1 107 120 2 1 7 1 213 220 3 1 15 138 30 5 0 6 2 529 545 4 1 3 0 352 375 3 −4 1 1 162 152 4 2 7 1 91 93 2 215 1 34 46 6 1 6 2 238 248 11 2 3 0 39 35 3 −2 1 1 338 350 3 3 7 1 136137 1 3 15 1 27 4 5 2 6 2 152 158 2 3 3 0 58 55 2 −1 1 1 1141 1205 14 47 1 174 165 1 −2 16 1 24 27 7 3 6 2 131 128 1 4 3 0 84 80 1 1 1 1 11341206 11 5 7 1 160 158 2 −1 16 1 27 13 6 4 6 2 77 77 2 5 3 0 43 42 8 4 11 163 152 1 6 7 1 33 17 24 0 16 1 18 4 17 5 6 2 61 66 2 6 3 0 54 51 5 51 1 109 120 2 −6 8 1 61 46 10 1 16 1 33 13 8 6 6 2 69 66 3 7 3 0 34 7 76 1 1 56 55 11 −5 8 1 65 60 11 2 16 1 20 28 6 −6 7 2 39 49 13 0 4 0 114118 2 7 1 1 19 16 18 −4 8 1 52 51 2 0 17 1 24 32 5 −5 7 2 96 98 3 1 4 017 3 3 −7 2 1 38 15 7 −3 8 1 150 145 1 1 17 1 17 3 17 −4 7 2 65 63 2 2 40 88 82 1 −6 2 1 41 44 4 −2 8 1 86 88 1 0 0 2 393 405 5 −3 7 2 99 90 2 44 0 87 87 1 −5 2 1 28 16 5 −1 8 1 68 69 5 1 0 2 332 336 8 −2 7 2 141 1572 5 4 0 19 15 18 −4 2 1 256 252 5 0 8 1 378 391 3 2 0 2 412 409 8 −1 7 2442 439 5 6 4 0 99 104 5 −3 2 1 108 98 2 1 8 1 69 68 2 4 0 2 137 137 3 07 2 252 268 2 7 4 0 66 56 4 −2 2 1 98 100 2 2 8 1 89 87 2 −6 1 2 34 44 51 7 2 447 439 14 1 5 0 17 4 7 −1 2 1 465 481 4 3 8 1 152 145 1 −5 1 2114 119 4 2 7 2 146 157 2 2 5 0 72 64 1 0 2 1 15 2 3 4 8 1 54 51 6 −4 12 52 49 2 3 7 2 98 89 1 3 5 0 108 106 6 1 2 1 478 482 4 5 8 1 67 59 4 −21 2 174 178 1 4 7 2 69 63 2 4 5 0 86 82 1 2 2 1 93 99 2 6 8 1 46 46 4 −11 2 599 599 5 5 7 2 102 97 2 5 5 0 34 29 3 4 2 1 257 252 2 −6 9 1 37 2812 0 1 2 166 164 2 6 7 2 51 48 4 6 5 0 29 22 6 5 2 1 17 16 8 −5 9 1 8471 3 2 1 2 178 178 2 −6 8 2 20 16 13 7 5 0 57 41 6 6 2 1 41 44 6 −4 9 1105 103 1 4 1 2 50 49 2 −5 8 2 53 52 4 0 6 0 645 708 8 7 2 1 17 14 16 −39 1 156 151 1 5 1 2 119 118 2 −4 8 2 118 118 1 1 6 0 360 437 50 −7 3 141 49 6 −2 9 1 54 46 1 6 1 2 47 44 3 −3 8 2 92 90 4 2 6 0 101 96 21 −6 31 52 50 4 −1 9 1 194 201 8 7 1 2 59 55 5 −2 8 2 40 37 2 3 6 0 36 39 3 −53 1 171 175 1 0 9 1 227 233 2 −7 2 2 39 34 6 −1 8 2 325 343 4 4 6 0 1917 4 −4 3 1 239 231 3 1 9 1 190 201 7 −6 2 2 106 111 2 0 8 2 165 186 2 56 0 80 76 5 −3 3 1 457 454 6 2 9 1 50 46 3 −5 2 2 211 211 3 1 8 2 312344 4 6 6 0 48 44 4 −2 3 1 306 308 4 3 9 1 157 151 1 −4 2 2 74 77 1 2 82 38 37 1 1 7 0 31 28 3 −1 3 1 375 403 4 4 9 1 114 103 1 −3 2 2 385 3735 3 8 2 92 91 1 2 7 0 110 128 25 0 3 1 358 411 19 5 9 1 74 71 5 −2 2 296 91 1 4 8 2 118 118 3 3 7 0 72 70 1 1 3 1 394 402 3 6 9 1 36 28 6 −1 22 614 632 19 5 8 2 54 52 4 4 7 0 79 78 2 2 3 1 304 307 4 −5 10 1 54 57 40 2 2 371 373 7 6 8 2 32 16 15 5 7 0 171 167 2 3 3 1 472 455 6 −4 10 1107 110 3 1 2 2 623 632 8 −6 9 2 76 71 5 6 7 0 49 48 4 4 3 1 240 231 2−3 10 1 168 166 1 2 2 2 105 92 2 −5 9 2 42 36 6 0 8 0 134 137 2 5 3 1169 176 3 −2 10 1 79 79 3 4 2 2 80 78 1 −4 9 2 170 164 2 1 8 0 226 226 86 3 1 44 50 5 −1 10 1 139 149 2 5 2 2 211 211 6 −3 9 2 83 82 1 2 8 0 211196 3 7 3 1 54 49 5 0 10 1 127 138 1 6 2 2 116 111 3 −2 9 2 44 39 2 3 80 66 64 1 −7 4 1 46 41 5 1 10 1 145 148 1 7 2 2 34 35 7 −1 9 2 77 79 1 48 0 315 302 2 −6 4 1 81 84 2 2 10 1 74 79 1 −7 3 2 69 71 4 0 9 2 84 93 35 8 0 67 63 3 −5 4 1 34 26 20 3 10 1 168 165 1 −6 3 2 75 81 4 1 9 2 8079 2 6 8 0 38 28 6 −4 4 1 171 165 1 4 10 1 107 110 2 −5 3 2 112 104 1 29 2 40 38 1 1 9 0 247 260 7 −3 4 1 189 193 3 5 10 1 62 57 4 −4 3 2 147144 3 3 9 2 85 82 1 2 9 0 243 244 2 −2 4 1 199 199 3 −5 11 1 22 6 13 −33 2 190 177 3 4 9 2 172 164 4 3 9 0 193 186 2 −1 4 1 346 367 4 −4 11 177 79 2 −2 3 2 105 107 2 5 9 2 25 36 9 4 9 0 405 398 3 0 4 1 450 520 19−3 11 1 51 50 1 −1 3 2 395 396 14 6 9 2 77 71 6 5 9 0 8 2 8 1 4 1 356368 13 −2 11 1 70 71 1 0 3 2 252 272 12 −5 10 2 29 11 11 6 9 0 81 75 7 24 1 195 200 2 −1 11 1 92 93 2 1 3 2 391 396 5 −4 10 2 100 99 4 0 10 0119 124 2 3 4 1 182 194 3 0 11 1 98 100 2 2 3 2 108 107 2 −3 10 2 176168 3 1 10 0 54 49 1 4 4 1 176 166 3 1 11 1 94 93 2 4 3 2 146 144 1 −210 2 145 135 2 2 10 0 127 124 1 5 4 1 27 26 4 2 11 1 68 71 1 5 3 2 108103 4 −1 10 2 167 159 3 3 10 0 116 115 1 6 4 1 83 84 3 3 11 1 52 50 2 63 2 89 81 3 0 10 2 187 189 3 4 10 0 26 0 5 7 4 1 37 41 6 4 11 1 79 79 27 3 2 75 70 3 1 10 2 168 158 2 5 10 0 63 63 4 −7 5 1 58 45 5 5 11 1 6 65 −6 4 2 95 101 2 2 10 2 142 135 1 1 11 0 77 75 2 −6 5 1 26 18 16 −5 121 49 46 8 −5 4 2 75 79 4 3 10 2 177 168 1 2 11 0 46 45 3 −5 5 1 79 76 2−4 12 1 40 35 4 −4 4 2 172 175 3 4 10 2 99 100 3 3 11 0 15 15 5 −4 5 144 46 1 −3 12 1 52 55 2 −3 4 2 241 230 3 5 10 2 33 11 14 4 11 0 142 1412 −3 5 1 136 137 2 −2 12 1 162 161 1 −2 4 2 431 439 5 −5 11 2 69 66 3 511 0 46 35 14 −2 5 1 337 336 4 −1 12 1 159 150 4 −1 4 2 58 62 2 −4 11 249 45 3 0 12 0 58 55 3 −1 5 1 171 174 2 0 12 1 113 117 2 0 4 2 242 26820 −3 11 2 87 87 2 1 12 0 67 69 1 0 5 1 274 294 2 1 12 1 163 151 3 1 4 269 63 1 −2 11 2 106 103 4 2 12 0 145 145 1 1 5 1 174 174 2 2 12 1 158161 1 2 4 2 438 438 7 −1 11 2 108 119 2 3 12 0 43 40 4 2 5 1 343 336 4 312 1 56 55 2 3 4 2 247 229 3 0 11 2 96 88 2 4 12 0 32 24 4 3 5 1 126 1371 4 12 1 32 35 10 4 4 2 177 175 2 1 11 2 112 118 1 5 12 0 45 36 4 4 5 145 46 2 5 12 1 48 46 13 5 4 2 80 79 2 2 11 2 105 104 1 1 13 0 26 9 7 5 51 82 76 3 −4 13 1 41 23 9 6 4 2 106 101 3 3 11 2 87 87 2 2 13 0 161 1641 6 5 1 24 18 14 −3 13 1 67 71 2 7 4 2 50 40 5 4 11 2 41 45 4 3 13 0 137141 1 7 5 1 68 45 4 −2 13 1 45 47 2 −6 5 2 85 79 4 5 11 2 70 66 3 4 13 043 42 9 −6 6 1 87 91 4 −1 13 1 49 38 2 −5 5 2 94 96 7 −5 12 2 59 63 20 014 0 79 84 2 −5 6 1 125 128 2 0 13 1 23 25 3 −4 5 2 188 188 1 −4 12 2 6559 3 1 14 0 40 32 2 −4 6 1 61 61 1 1 13 1 54 38 5 −3 5 2 162 167 3 −3 122 46 48 2 2 14 0 32 26 4 −3 6 1 77 73 1 2 23 1 50 47 4 −2 5 2 181 176 3−2 12 2 39 46 6 3 14 0 87 89 2 −2 6 1 73 71 2 3 13 1 70 71 2 −1 5 2 151146 2 −1 12 2 43 27 9 4 14 0 49 43 4 −1 6 1 327 325 4 4 13 1 41 23 7 0 52 901 990 15 0 12 2 21 13 3 1 12 2 38 27 9 1 4 3 305 297 3 0 11 3 72 671 1 3 4 316 326 2 −2 10 4 70 68 2 2 12 2 41 46 2 2 4 3 115 120 2 1 11 365 63 2 4 3 4 11 8 10 −1 10 4 81 80 1 3 12 2 43 48 2 4 4 3 86 85 2 2 113 141 137 2 5 3 4 38 44 3 0 10 4 49 49 1 4 12 2 66 59 3 5 4 3 139 136 33 11 3 159 153 1 6 3 4 81 78 3 1 10 4 81 79 3 5 12 2 53 63 9 6 4 3 72 684 4 11 3 130 130 2 7 3 4 42 41 5 2 10 4 70 67 2 4 13 2 34 34 8 7 4 3 4842 5 5 11 3 96 92 2 −6 4 4 84 94 3 3 10 4 105 104 2 3 13 2 87 90 2 −6 53 52 51 11 −5 12 3 38 48 8 −5 4 4 28 32 4 4 10 4 77 68 2 2 13 2 36 20 5−5 5 3 172 171 2 −4 12 3 29 25 5 −4 4 4 142 142 1 5 10 4 68 60 3 1 13 2116 120 2 −4 5 3 76 72 2 −3 12 3 135 135 4 −3 4 4 235 222 3 −5 11 4 119116 2 0 13 2 66 62 1 −3 5 3 21 12 7 −2 12 3 80 84 2 −2 4 4 186 180 2 −411 4 24 11 7 1 13 2 117 120 3 −2 5 3 223 216 3 −1 12 3 181 175 3 −1 4 4400 390 8 −3 11 4 113 111 2 2 13 2 30 20 7 −1 5 3 186 196 2 0 12 3 45 492 0 4 4 327 325 3 −2 11 4 86 83 2 3 13 2 89 90 2 0 5 3 733 738 46 1 12 3176 174 3 1 4 4 392 390 9 −1 11 4 164 160 2 4 13 2 38 34 5 1 5 3 197 1962 2 12 3 81 84 3 2 4 4 186 180 6 0 11 4 109 111 1 4 14 2 60 57 8 2 5 3225 217 3 3 12 3 133 136 1 3 4 4 208 222 3 1 11 4 162 161 2 3 14 2 41 433 3 5 3 15 12 10 4 12 3 15 24 14 4 4 4 153 142 2 2 11 4 83 83 1 2 14 256 61 2 4 5 3 79 73 2 5 12 3 50 48 3 5 4 4 31 32 4 3 11 4 117 111 1 1 142 34 25 3 5 5 3 176 171 4 −4 13 3 25 20 13 6 4 4 90 94 3 4 11 4 32 12 60 14 2 92 92 1 6 5 3 54 51 5 −3 13 3 64 62 2 7 4 4 25 6 10 5 11 4 112115 2 1 14 2 22 25 6 −6 6 3 52 51 7 −2 13 3 38 36 2 −6 5 4 84 99 4 −5 124 59 47 8 2 14 2 61 61 4 −5 6 3 93 93 3 −1 13 3 49 48 2 −5 5 4 133 138 5−4 12 4 19 4 10 3 14 2 41 42 4 −4 6 3 120 114 2 0 13 3 34 24 5 −4 5 4 5759 2 −3 12 4 116 121 2 4 14 2 53 57 5 −3 6 3 62 60 2 1 13 3 44 48 3 −3 54 147 150 2 −2 12 4 44 32 5 3 15 2 36 36 4 −2 6 3 238 243 3 2 13 3 48 3612 −2 5 4 177 182 3 −1 12 4 125 117 3 2 15 2 47 44 4 −1 6 3 88 86 2 3 133 63 62 3 −1 5 4 258 237 2 0 12 4 64 62 2 1 15 2 21 10 7 0 6 3 136 146 14 13 3 38 20 8 0 5 4 339 335 20 1 12 4 119 117 1 0 15 2 33 36 3 1 6 3 9284 1 −4 14 3 37 38 8 1 5 4 247 237 2 2 12 4 41 32 3 1 15 2 25 10 5 2 6 3233 242 3 −3 14 3 96 96 2 2 5 4 166 181 1 3 12 4 120 121 2 2 15 2 40 444 3 6 3 61 61 2 −2 14 3 94 106 2 3 5 4 152 151 2 4 12 4 31 4 31 3 15 234 37 4 4 6 3 125 114 2 −1 14 3 31 18 4 4 5 4 60 59 2 5 12 4 46 47 5 216 2 24 16 5 5 6 3 97 93 2 0 14 3 27 29 4 5 5 4 132 138 2 −4 13 4 59 563 1 16 2 27 29 6 6 6 3 58 51 4 1 14 3 24 19 5 6 5 4 94 99 3 −3 13 4 7780 1 0 16 2 37 17 4 −6 7 3 32 23 9 2 14 3 101 106 3 −6 6 4 66 73 11 −213 4 98 98 1 1 16 2 29 29 3 −5 7 3 53 57 2 3 14 3 99 96 5 −5 6 4 59 58 3−1 13 4 37 42 6 2 16 2 23 16 6 −4 7 3 232 230 2 4 14 3 37 38 4 −4 6 4 7779 2 0 13 4 58 64 3 0 17 2 19 14 8 −3 7 3 59 56 2 −3 15 3 35 35 9 −3 6 467 64 1 1 13 4 40 42 3 1 17 2 37 28 6 −2 7 3 171 181 3 −2 15 3 36 33 3−2 6 4 173 169 3 2 13 4 98 99 2 1 0 3 986 1006 11 −1 7 3 228 222 3 −1 153 32 21 6 −1 6 4 330 348 4 3 13 4 76 80 2 2 0 3 115 121 2 0 7 3 379 4033 0 15 3 39 34 3 0 6 4 55 58 4 4 13 4 50 57 7 4 0 3 324 311 5 1 7 3 230222 6 1 15 3 36 21 7 1 6 4 350 349 7 −4 14 4 62 58 6 6 0 3 57 51 14 2 73 167 180 3 2 15 3 31 33 6 2 6 4 157 169 2 −3 14 4 67 64 2 6 1 3 73 67 33 7 3 57 56 1 3 15 3 40 35 4 3 6 4 68 64 1 −2 14 4 22 14 5 5 1 3 253 2509 4 7 3 231 230 7 −2 16 3 34 35 2 4 6 4 82 79 6 −1 14 4 38 39 6 4 1 3176 170 3 5 7 3 59 57 3 −1 16 3 28 7 5 5 6 4 58 58 2 0 14 4 77 83 2 3 13 392 392 7 6 7 3 38 23 16 0 16 3 52 55 2 6 6 4 77 73 4 1 14 4 38 39 4 21 3 207 207 2 −6 8 3 32 28 10 1 16 3 29 7 6 −6 7 4 55 36 6 2 14 4 20 159 1 1 3 101 95 2 −5 8 3 31 15 4 2 16 3 42 36 4 −5 7 4 101 105 3 3 14 464 64 3 0 1 3 1115 1114 19 −4 8 3 73 78 2 0 17 3 68 76 3 −4 7 4 57 57 24 14 4 56 59 4 1 1 3 97 96 2 −3 8 3 193 191 2 0 0 4 372 431 7 −3 7 4 3536 1 −3 15 4 42 42 2 2 1 3 205 206 2 −2 8 3 189 190 4 1 0 4 549 576 4 −27 4 147 139 3 −2 15 4 56 66 5 4 1 3 176 169 2 −1 8 3 310 324 4 2 0 4 6465 1 −1 7 4 302 287 4 −1 15 4 49 55 8 5 1 3 252 249 9 0 8 3 234 243 11 40 4 38 42 23 0 7 4 175 175 14 0 15 4 44 36 3 6 1 3 69 66 2 1 8 3 308 3257 5 0 4 99 100 3 1 7 4 299 287 4 1 15 4 61 55 3 7 1 3 42 18 6 2 8 3 185191 3 6 0 4 116 121 7 2 7 4 142 139 2 2 15 4 54 66 4 6 2 3 77 80 2 3 8 3188 191 2 −6 1 4 66 64 5 3 7 4 39 36 2 3 15 4 46 42 7 5 2 3 59 70 2 4 83 79 78 2 −5 1 4 100 102 2 4 7 4 58 57 2 −2 16 4 36 41 8 4 2 3 87 91 3 58 3 27 15 22 −4 1 4 90 77 2 5 7 4 108 106 2 −1 16 4 55 66 2 3 2 3 223231 3 6 8 3 25 28 8 −3 1 4 141 148 1 6 7 4 49 36 5 0 16 4 24 6 6 2 2 3377 364 3 −6 9 3 59 52 6 −2 1 4 112 111 2 −6 8 4 45 36 7 1 16 4 61 65 41 2 3 715 744 16 −5 9 3 82 80 4 −1 1 4 489 481 4 −5 8 4 176 177 2 2 16 432 41 7 0 2 3 1539 1543 19 −4 9 3 261 247 2 0 1 4 731 731 10 −4 8 4 8893 1 1 0 5 97 112 2 1 2 3 723 744 8 −3 9 3 116 117 3 1 1 4 473 481 6 −38 4 207 208 6 2 0 5 313 371 45 2 2 3 359 364 4 −2 9 3 72 67 2 2 1 4 108111 2 −2 8 4 119 121 3 3 0 5 180 174 2 4 2 3 83 91 1 −1 9 3 40 31 3 4 14 90 77 4 −1 8 4 231 230 6 4 0 5 115 109 2 5 2 3 63 70 1 0 9 3 52 55 2 51 4 102 103 5 0 8 4 180 186 10 5 0 5 316 289 4 6 2 3 86 80 3 1 9 3 32 311 6 1 4 74 64 4 1 8 4 236 230 7 −6 1 5 62 62 4 7 2 3 25 20 11 2 9 3 6967 1 7 1 4 38 45 7 2 8 4 124 122 2 −5 1 5 209 197 3 6 3 3 79 84 4 3 9 3116 117 1 −6 2 4 30 20 9 3 8 4 211 208 4 −4 1 5 136 128 2 5 3 3 127 1212 4 9 3 256 247 4 −5 2 4 203 190 3 4 8 4 91 93 2 −3 1 5 101 112 2 4 3 3217 214 8 5 9 3 83 80 5 −4 2 4 136 129 2 5 8 4 181 177 2 −2 1 5 261 2562 3 3 3 87 77 2 6 9 3 66 52 9 −3 2 4 329 324 3 6 8 4 46 36 5 −1 1 5 290294 6 2 3 3 217 219 2 −5 10 3 65 65 4 −2 2 4 236 241 2 −6 9 4 48 41 7 01 5 244 248 2 1 3 3 676 688 22 −4 10 3 146 144 1 −1 2 4 471 497 15 −5 94 51 48 3 1 1 5 287 295 3 0 3 3 461 472 10 −3 10 3 37 35 2 0 2 4 952 92220 −4 9 4 107 104 3 2 1 5 249 257 3 1 3 3 675 687 5 −2 10 3 85 74 3 1 24 483 497 8 −3 9 4 74 74 1 4 1 5 135 128 2 2 3 3 228 219 3 −1 10 3 251228 2 2 2 4 232 242 3 −2 9 4 101 98 2 5 1 5 201 197 3 4 3 3 220 213 2 010 3 43 41 1 4 2 4 125 129 1 −1 9 4 72 69 1 6 1 5 76 61 4 5 3 3 130 1207 1 10 3 237 228 8 5 2 4 203 191 3 0 9 4 176 174 4 7 1 5 25 46 14 6 3 381 84 3 2 10 3 83 74 1 6 2 4 27 20 11 1 9 4 68 69 1 −5 2 5 118 119 2 7 33 54 45 5 3 10 3 34 35 2 7 2 4 38 9 7 2 9 4 102 97 4 −4 2 5 32 44 4 6 43 69 68 3 4 10 3 147 144 3 −6 3 4 82 78 3 3 9 4 76 73 2 −3 2 5 224 218 25 4 3 135 136 2 5 10 3 74 65 3 −5 3 4 44 44 7 4 9 4 104 104 2 −2 2 5 262273 4 4 4 3 79 85 1 −5 11 3 96 92 4 −4 3 4 15 9 9 5 9 4 53 48 5 −1 2 5713 749 40 3 4 3 109 103 2 −4 11 3 130 130 3 −3 3 4 275 287 4 6 9 4 3641 6 0 2 5 403 403 3 2 4 3 119 121 2 −3 11 3 157 153 4 −2 3 4 262 259 7−5 10 4 59 60 8 1 2 5 716 750 7 1 4 3 300 297 9 −2 11 3 148 137 2 −1 3 4315 325 15 −4 10 4 74 68 3 2 2 5 262 272 3 0 4 3 261 268 3 −1 11 3 58 631 0 3 4 241 241 4 −3 10 4 104 104 2 4 2 5 41 44 3 5 2 5 124 119 2 −3 105 73 75 1 7 2 6 35 28 8 4 10 6 59 52 4 −3 4 7 172 165 1 6 2 5 66 56 4 −210 5 32 29 2 −4 3 6 147 143 2 5 10 6 92 97 2 −2 4 7 151 142 2 7 2 5 3837 6 −1 10 5 109 112 2 −3 3 6 127 134 2 −5 11 6 34 22 7 −1 4 7 314 293 35 3 5 78 76 3 0 10 5 20 21 5 −2 3 6 361 357 3 −4 11 6 129 126 2 0 4 7148 130 1 4 3 5 105 98 2 1 10 5 111 112 2 −1 3 6 287 275 2 −3 11 6 30 296 1 4 7 302 292 4 3 3 5 226 216 2 2 10 5 39 29 8 0 3 6 283 282 12 −2 116 113 115 1 3 4 7 174 165 2 2 3 5 206 194 4 3 10 5 70 75 1 1 3 6 273 2762 −1 11 6 170 176 5 4 4 7 75 79 3 1 3 5 158 156 2 4 10 5 43 41 4 2 3 6356 357 4 0 11 6 23 20 2 5 4 7 80 78 3 0 3 5 353 335 5 5 10 5 108 110 44 3 6 145 143 3 1 11 6 170 176 2 6 4 7 82 81 4 1 3 5 159 156 3 −5 11 533 27 6 5 3 6 201 198 3 2 11 6 111 116 2 −4 5 7 61 60 3 4 3 5 99 97 3 −411 5 90 84 2 6 3 6 61 50 5 3 11 6 31 29 16 −3 5 7 107 104 1 5 3 5 80 763 −3 11 5 29 27 3 −3 4 6 86 87 2 4 11 6 124 125 3 −2 5 7 162 153 4 6 3 560 51 5 −2 11 5 104 99 1 −2 4 6 113 101 1 5 11 6 23 22 7 −1 5 7 152 1402 7 3 5 32 6 8 −1 11 5 97 106 2 −1 4 6 539 523 13 −4 12 6 38 33 6 0 5 7181 186 28 4 4 5 20 21 19 0 11 5 18 2 8 0 4 6 65 59 1 −3 12 6 129 128 41 5 7 145 139 1 3 4 5 203 196 3 1 11 5 102 106 2 1 4 6 530 523 6 −2 12 6100 93 3 2 5 7 152 153 2 2 4 5 248 242 5 2 11 5 100 100 1 2 4 6 102 1012 −1 12 6 91 89 3 3 5 7 106 104 2 1 4 5 73 71 2 3 11 5 39 27 6 3 4 6 8787 2 0 12 6 111 112 1 4 5 7 63 60 1 0 4 5 158 171 5 4 11 5 83 84 3 4 4 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154 158 4 3 3 13 24 21 3 1 0 14 78 71 1 1 3 11 2319 2 0 12 11 25 18 10 3 7 12 78 78 3 4 3 13 51 61 4 2 0 14 118 114 1 0 311 126 134 3 1 12 11 62 64 3 4 7 12 44 48 5 5 3 13 54 62 5 3 0 14 119124 2 1 3 11 25 20 2 2 12 11 77 77 10 5 7 12 25 32 10 −4 4 13 76 80 6 40 14 102 97 2 2 3 11 47 47 1 3 12 11 22 18 18 −4 8 12 68 72 4 −3 4 13 5649 2 5 0 14 43 71 8 3 3 11 112 117 3 −3 13 11 49 56 6 −3 8 12 71 67 2 −24 13 55 57 1 −5 1 14 31 29 10 4 3 11 73 74 3 −2 13 11 53 55 4 −2 8 12 8784 1 −1 4 13 75 71 1 −4 1 14 36 44 3 5 3 11 45 52 5 −1 13 11 27 20 6 −18 12 90 89 1 0 4 13 18 19 3 −3 1 14 35 33 4 4 4 11 65 66 2 0 13 11 50 406 0 8 12 66 60 2 1 4 13 77 72 2 −2 1 14 23 8 4 3 4 11 189 186 3 1 13 1136 20 8 1 8 12 90 89 1 2 4 13 59 58 2 −1 1 14 60 60 2 2 4 11 26 24 3 213 11 40 55 12 2 8 12 85 84 2 3 4 13 54 49 2 0 1 14 85 81 1 1 4 11 101100 1 3 13 11 55 56 7 3 8 12 72 67 4 4 4 13 72 80 3 1 1 14 57 61 1 0 411 79 83 1 −2 14 11 25 13 7 4 8 12 66 72 5 5 4 13 24 32 11 2 1 14 22 7 31 4 11 101 100 1 −1 14 11 26 28 10 5 8 12 13 26 12 −4 5 13 37 38 4 3 114 38 33 5 2 4 11 26 24 5 0 14 11 36 41 4 −4 9 12 94 92 2 −3 5 13 80 792 4 1 14 38 44 4 3 4 11 185 186 3 1 14 11 18 28 17 −3 9 12 113 114 2 −25 13 81 79 1 5 1 14 4 28 4 4 4 11 63 66 3 2 14 11 27 14 7 −2 9 12 21 254 −1 5 13 26 26 2 −5 2 14 76 84 4 5 4 11 47 52 5 0 0 12 640 627 11 −1 912 112 107 2 0 5 13 266 274 2 −4 2 14 75 78 2 4 5 11 17 12 8 1 0 12 2727 2 0 9 12 58 52 1 1 5 13 32 26 4 −3 2 14 215 215 7 3 5 11 106 101 4 20 12 153 155 1 1 9 12 109 107 2 2 5 13 84 79 2 −2 2 14 79 79 2 2 5 11 98100 1 3 0 12 93 99 3 2 9 12 20 25 6 3 5 13 78 79 3 −1 2 14 152 146 1 1 511 136 133 2 4 0 12 110 113 2 3 9 12 107 114 3 4 5 13 39 38 6 0 2 14 191 4 0 5 11 78 75 1 −4 1 12 191 207 3 4 9 12 84 92 4 5 5 13 53 60 5 1 214 151 146 3 1 5 11 134 133 2 −3 1 12 150 158 3 −4 10 12 26 25 7 −4 6 1381 88 8 2 2 14 84 79 1 2 5 11 94 101 2 −2 1 12 42 37 2 −3 10 12 33 13 13−3 6 13 44 36 5 3 2 14 212 215 1 3 5 11 105 101 2 −1 1 12 132 137 2 −210 12 71 68 2 −2 6 13 111 110 1 4 2 14 73 78 2 4 5 11 30 12 6 0 1 12 130121 1 −1 10 12 72 72 1 −1 6 13 143 140 1 5 2 14 54 84 5 5 5 11 46 42 6 11 12 131 137 1 0 10 12 161 162 2 0 6 13 23 11 3 −5 3 14 52 44 6 4 6 1174 73 2 2 1 12 38 37 3 1 10 12 70 71 2 1 6 13 142 140 2 −4 3 14 33 39 53 6 11 63 60 3 3 1 12 145 157 4 2 10 12 71 69 2 2 6 13 112 110 1 −3 3 1449 48 2 2 6 11 34 33 3 4 1 12 197 207 3 3 10 12 15 13 15 3 6 13 47 36 5−2 3 14 57 50 5 1 6 11 141 145 1 −4 2 12 60 60 2 4 10 12 14 25 14 4 6 1376 88 3 −1 3 14 83 81 1 0 6 11 47 30 3 −3 2 12 60 61 2 −3 11 12 32 17 95 6 13 24 44 11 0 3 14 63 65 1 1 6 11 142 145 2 −2 2 12 115 112 1 −2 1112 46 48 5 −4 7 13 55 64 3 1 3 14 84 82 3 2 6 11 32 33 2 −1 2 12 192 1982 −1 11 12 56 51 3 −3 7 13 100 95 2 2 3 14 54 50 1 3 6 11 60 60 3 0 2 12104 106 1 0 11 12 35 26 4 −2 7 13 110 107 2 3 3 14 53 48 3 4 6 11 66 724 1 2 12 195 198 2 1 11 12 48 51 3 −1 7 13 80 80 2 4 3 14 31 39 8 5 3 1426 44 11 2 1 15 160 151 2 1 11 15 25 20 8 −2 10 16 73 78 4 1 0 18 129120 2 5 4 14 46 21 6 3 1 15 136 131 1 2 11 15 6 38 5 −1 10 16 25 23 6 20 18 197 195 2 4 4 14 23 12 8 4 1 15 49 57 5 −1 12 15 35 41 6 0 10 16 2513 7 3 0 18 23 20 11 3 4 14 54 43 5 5 1 15 35 56 11 0 12 15 42 42 4 1 1016 21 23 9 −4 1 18 48 50 4 2 4 14 34 19 3 −4 2 15 47 46 4 1 12 15 42 415 2 10 16 72 78 5 −3 1 18 44 41 4 1 4 14 49 46 1 −3 2 15 38 35 3 0 0 1627 8 3 −1 11 16 28 13 12 −2 1 18 88 80 2 0 4 14 54 52 2 −2 2 15 42 37 31 0 16 70 62 1 0 11 16 30 13 5 −1 1 18 52 49 2 1 4 14 53 46 2 −1 2 15170 165 1 2 0 16 31 18 3 1 11 16 17 14 17 0 1 18 26 23 4 2 4 14 28 19 60 2 15 166 157 2 3 0 16 91 95 1 0 12 16 29 18 7 1 1 18 56 49 2 3 4 14 4543 3 1 2 15 172 165 3 4 0 16 13 12 12 1 0 17 19 2 5 2 1 18 83 80 3 5 414 31 21 7 2 2 15 41 37 4 −4 1 16 60 73 3 2 0 17 82 71 3 3 1 18 40 41 64 5 14 33 43 5 3 2 15 33 36 3 −3 1 16 64 62 2 3 0 17 78 73 2 4 1 18 3350 6 3 5 14 59 49 3 4 2 15 38 46 5 −2 1 16 133 123 1 4 0 17 15 27 15 −42 18 34 39 14 2 5 14 29 23 3 5 2 15 45 37 9 −1 1 16 105 101 1 −4 1 17 3032 5 −3 2 18 17 3 14 1 5 14 52 50 1 −5 3 15 60 57 5 0 1 16 32 20 3 −3 117 28 32 6 −2 2 18 135 126 1 0 5 14 27 30 3 −4 3 15 39 45 3 1 1 16 109101 3 −2 1 17 150 139 1 −1 2 18 54 47 2 1 5 14 57 50 4 −3 3 15 47 36 3 21 16 131 123 1 −1 1 17 114 111 1 0 2 18 23 20 6 2 5 14 37 23 11 −2 3 15134 131 2 3 1 16 60 62 4 0 1 17 26 1 7 1 2 18 52 47 2 3 5 14 56 50 2 −13 15 75 75 1 4 1 16 71 73 3 1 1 17 118 111 1 2 2 18 137 126 3 4 5 14 4042 6 0 3 15 180 165 1 −4 2 16 55 59 4 2 1 17 147 139 2 3 2 18 19 3 19 46 14 58 57 3 1 3 15 78 74 1 −3 2 16 64 58 3 3 1 17 28 32 5 4 2 18 20 3920 3 6 14 97 96 2 2 3 15 133 131 1 −2 2 16 69 61 1 4 1 17 37 32 7 −4 318 43 29 7 2 6 14 104 102 1 3 3 15 33 36 3 −1 2 16 152 147 1 −4 2 17 3533 4 −3 3 18 25 5 6 1 6 14 42 41 2 4 3 15 40 46 6 0 2 16 36 22 2 −3 2 1742 22 4 −2 3 18 63 57 2 0 6 14 21 8 4 5 3 15 43 57 6 1 2 16 153 147 3 −22 17 87 78 2 −1 3 18 29 23 4 1 6 14 42 41 2 −5 4 15 32 8 10 2 2 16 66 611 −1 2 17 63 60 1 0 3 18 54 53 4 2 6 14 106 102 1 −4 4 15 41 33 8 3 2 1657 58 4 0 2 17 28 16 5 2 3 18 49 57 3 3 6 14 86 96 3 −3 4 15 80 81 4 4 216 45 59 4 1 2 17 60 60 3 3 3 18 16 4 15 4 6 14 54 56 5 −2 4 15 93 94 3−4 3 16 40 46 9 2 2 17 87 79 3 4 3 18 27 29 18 4 7 14 73 82 9 −1 4 15 2416 3 −3 3 16 64 59 2 3 2 17 23 22 7 −3 4 18 14 4 14 3 7 14 32 34 7 0 415 90 92 1 −2 3 16 25 16 3 4 2 17 20 33 19 −2 4 18 52 45 3 2 7 14 61 651 1 4 15 38 16 4 −1 3 16 137 133 1 −4 3 17 30 11 6 −1 4 18 35 33 3 1 714 176 179 1 2 4 15 96 94 5 0 3 16 36 20 2 −3 3 17 70 67 4 0 4 18 48 472 0 7 14 25 5 3 3 4 15 84 81 2 1 3 16 137 133 3 −2 3 17 57 46 2 1 4 1842 32 4 1 7 14 181 179 2 4 4 15 25 33 12 2 3 16 24 17 12 −1 3 17 55 55 12 4 18 58 45 3 2 7 14 63 65 2 −4 5 15 45 33 4 3 3 16 59 59 3 0 3 17 4028 3 4 4 18 31 44 10 3 7 14 29 34 10 −3 5 15 60 64 2 4 3 16 40 46 7 1 317 58 55 3 −3 5 18 43 35 3 4 7 14 73 81 4 −2 5 15 123 127 1 −4 4 16 4138 10 2 3 17 54 46 4 −2 5 18 52 43 5 4 8 14 31 26 7 −1 5 15 46 48 1 −3 416 58 55 2 3 3 17 60 66 2 −1 5 18 53 49 3 3 8 14 50 65 3 0 5 15 116 1092 −2 4 16 104 97 1 −4 4 17 39 38 5 0 5 18 52 48 2 2 8 14 72 69 2 1 5 1550 48 2 −1 4 16 80 75 1 −3 4 17 46 43 3 1 5 18 53 49 5 1 8 14 71 68 1 25 15 124 127 2 0 4 16 47 42 2 −2 4 17 60 57 3 2 5 18 46 43 3 0 8 14 102107 1 3 5 15 59 64 3 1 4 16 81 75 2 −1 4 17 88 90 1 3 5 18 36 35 8 1 814 70 68 3 4 5 15 4 33 4 2 4 16 105 97 3 0 4 17 12 5 11 −3 6 18 23 32 72 8 14 71 69 2 −4 6 15 43 36 7 3 4 16 54 54 4 1 4 17 89 90 2 −2 6 18 6566 3 3 8 14 59 64 5 −3 6 15 38 39 7 4 4 16 27 38 9 2 4 17 55 57 2 −1 618 41 37 4 4 8 14 4 26 4 −2 6 15 76 73 1 −4 5 16 41 38 4 3 4 17 44 43 70 6 18 8 1 8 4 9 14 26 27 25 −1 6 15 112 121 1 −3 5 16 26 9 7 4 4 17 2438 13 1 6 18 27 37 8 3 9 14 37 11 5 0 6 15 58 57 2 −2 5 16 78 79 1 −4 517 52 49 3 2 6 18 62 66 2 2 9 14 62 66 3 1 6 15 116 121 2 −1 5 16 41 412 −3 5 17 43 36 4 −3 7 18 25 17 10 1 9 14 60 59 2 2 6 15 70 73 2 0 5 1684 88 1 −2 5 17 42 39 4 −2 7 18 45 38 3 0 9 14 34 28 3 3 6 15 33 39 8 15 16 44 40 2 −1 5 17 113 109 1 −1 7 18 30 17 5 1 9 14 57 59 2 4 6 15 1736 16 2 5 16 78 79 2 0 5 17 70 68 2 0 7 18 42 45 15 2 9 14 69 66 2 −4 715 43 39 5 3 5 16 25 9 8 1 5 17 113 109 2 1 7 18 31 17 19 4 9 14 16 2716 −3 7 15 33 31 12 4 5 16 26 38 10 2 5 17 36 39 4 2 7 18 36 38 3 3 1014 39 37 4 −2 7 15 83 78 2 −4 6 16 45 23 10 3 5 17 31 36 4 −2 8 18 52 513 2 10 14 37 37 4 −1 7 15 38 29 5 −3 6 16 63 66 2 4 5 17 38 49 6 −1 8 1861 61 3 1 10 14 46 43 2 0 7 15 54 45 3 −2 6 16 17 14 17 −3 6 17 45 7 5 08 18 55 65 3 0 10 14 72 75 2 1 7 15 44 29 8 −1 6 16 64 64 1 −2 6 17 2617 6 1 8 18 55 61 9 1 10 14 45 43 5 2 7 15 79 78 2 0 6 16 77 80 1 −1 617 56 54 2 2 8 18 47 51 3 2 10 14 33 37 4 3 7 15 6 31 5 1 6 16 69 64 2 06 17 65 56 3 −1 9 18 39 41 5 3 10 14 43 37 6 4 7 15 36 39 7 2 6 16 21 147 1 6 17 60 53 3 0 9 18 16 12 13 3 11 14 27 19 9 −4 8 15 35 32 6 3 6 1668 66 5 2 6 17 23 17 22 1 9 18 42 41 6 2 11 14 54 48 3 −3 8 15 48 53 6 46 16 9 23 9 3 6 17 18 7 18 1 0 19 15 6 15 1 11 14 51 53 3 −2 8 15 28 375 −4 7 16 28 3 7 −3 7 17 57 58 3 2 0 19 29 24 9 0 11 14 78 75 2 −1 8 1547 42 4 −3 7 16 50 41 3 −2 7 17 96 98 2 3 0 19 37 25 20 1 11 14 53 53 40 8 15 120 122 2 −2 7 16 74 76 2 −1 7 17 58 62 4 −3 1 19 63 66 2 2 11 1450 48 4 1 8 15 49 42 2 −1 7 16 96 97 2 0 7 17 97 96 5 −2 1 19 48 54 3 212 14 32 30 4 2 8 15 40 37 20 0 7 16 67 69 3 1 7 17 58 61 3 −1 1 19 5352 4 1 12 14 69 71 2 3 8 15 58 53 5 1 7 16 98 97 2 2 7 17 92 98 3 0 1 1917 8 12 0 12 14 22 4 8 −3 9 15 73 79 2 2 7 16 73 76 5 3 7 17 64 58 4 1 119 54 52 3 1 12 14 70 71 4 −2 9 15 37 39 5 3 7 16 25 41 13 −3 8 17 50 513 2 1 19 52 54 5 2 12 14 34 30 10 −1 9 15 55 53 6 4 7 16 4 3 4 −2 8 1778 82 2 3 1 19 59 66 2 1 13 14 33 39 5 0 9 15 36 27 4 −3 8 16 62 61 2 −18 17 31 32 8 −3 2 19 36 50 4 0 13 14 28 28 8 1 9 15 59 53 3 −2 8 16 3324 4 0 8 17 31 12 11 −2 2 19 48 34 3 1 13 14 15 39 14 2 9 15 41 39 7 −18 16 75 73 6 1 8 17 18 32 18 −1 2 19 34 29 4 1 0 15 309 302 3 3 9 15 6379 9 0 8 16 48 51 4 2 8 17 83 82 6 0 2 19 29 12 7 2 0 15 63 62 1 −3 1015 45 45 4 1 8 16 72 73 2 3 8 17 41 51 6 1 2 19 19 29 10 3 0 15 21 13 19−2 10 15 21 22 7 2 8 16 28 24 5 −2 9 17 49 54 3 2 2 19 34 34 6 4 0 15 3738 5 −1 10 15 59 48 3 3 8 16 62 62 4 −1 9 17 44 37 4 3 2 19 42 50 8 5 115 48 57 5 0 10 15 17 15 12 −3 9 16 23 28 8 0 9 17 35 1 9 −3 3 19 29 146 4 1 15 52 57 3 1 10 15 46 48 3 −2 9 16 43 47 3 1 9 17 36 37 4 −2 3 1935 24 4 3 1 15 138 130 3 2 10 15 24 22 7 −1 9 16 48 39 3 2 9 17 55 54 2−1 3 19 45 39 3 2 1 15 161 151 2 3 10 15 32 44 6 0 9 16 30 42 5 −1 10 1727 21 4 0 3 19 35 33 7 1 1 15 102 95 1 −2 11 15 39 38 3 1 9 16 42 39 3 010 17 22 2 10 1 3 19 30 39 5 0 1 15 93 90 1 −1 11 15 33 20 4 2 9 16 4047 3 1 10 17 18 21 12 2 3 19 41 24 4 1 1 15 101 95 2 0 11 15 22 21 8 3 916 26 28 12 0 0 18 27 7 6 −3 4 19 24 19 10 2 4 19 53 54 2 2 7 19 13 1512 0 2 20 34 10 13 2 5 20 21 25 6 2 2 21 36 32 16 1 4 19 33 31 3 −1 8 1957 58 3 1 2 20 27 41 7 −2 6 20 30 18 8 −2 3 21 39 37 6 0 4 19 50 51 4 08 19 43 41 4 2 2 20 71 71 3 −1 6 20 28 26 5 −1 3 21 37 17 6 1 4 19 20 3110 1 8 19 54 58 13 3 2 20 46 47 6 0 6 20 20 5 11 1 3 21 25 17 7 2 4 1946 54 5 0 0 20 41 45 5 −3 3 20 58 58 3 1 6 20 33 26 6 2 3 21 33 37 11 25 19 38 27 7 1 0 20 131 131 3 −2 3 20 39 37 4 0 7 20 21 2 15 −1 4 21 1419 14 1 5 19 20 10 9 2 0 20 46 36 4 −1 3 20 31 33 4 1 7 20 13 7 12 0 421 41 29 5 0 5 19 19 18 11 3 0 20 30 9 7 0 3 20 29 20 9 1 0 21 45 43 4 05 21 29 15 14 2 5 19 33 28 10 −3 1 20 38 13 8 1 3 20 41 33 4 2 0 21 3328 7 1 5 21 10 14 9 2 6 19 29 29 6 −2 1 20 63 65 4 2 3 20 36 37 3 −2 121 61 69 6 0 0 22 24 49 4 1 6 19 19 20 18 −1 1 20 34 37 5 −2 4 20 40 343 −1 1 21 50 51 6 1 0 22 44 35 5 0 6 19 29 12 6 0 1 20 38 43 3 −1 4 2053 47 4 0 1 21 21 19 6 −1 1 22 39 31 6 1 6 19 31 20 5 1 1 20 32 37 6 0 420 31 30 4 1 1 21 61 51 3 0 1 22 27 13 6 2 6 19 22 29 8 2 1 20 65 65 6 14 20 57 47 9 2 1 21 55 69 4 1 1 22 21 31 20 2 7 19 34 15 10 3 1 20 34 139 2 4 20 26 34 5 −2 2 21 27 32 7 0 2 22 35 37 6 1 7 19 16 23 15 −3 2 2046 47 10 −2 5 20 30 25 8 −1 2 21 44 47 3 0 7 19 27 20 15 −2 2 20 72 71 2−1 5 20 27 20 6 0 2 21 28 24 5 1 7 19 32 23 5 −1 2 20 40 41 3 0 5 20 1818 17 1 2 21 45 47 5

SYNTHESIS OF 2MBP EXAMPLE 3

[0029] The preparation of 2MBP having the basic structure I can beaccomplished by a common general method, i.e. the condensation of abicyclic Windaus-Grundmann type ketone II with the allylic phosphineoxide III to the corresponding 2-methylene-19-nor-vitamin D analog IVfollowed by deprotection at C-1 and C-3 in the latter compound IV toobtain compound I, i.e. 2MBP.

[0030] In the structures II, III, and IV groups Y₁ and Y₂ arehydroxy-protecting groups, it being also understood that anyfunctionalities that might be sensitive, or that interfere with thecondensation reaction, be suitably protected as is well-known in theart. The process shown above represents an application of the convergentsynthesis concept, which has been applied effectively for thepreparation of vitamin D compounds [e.g. Lythgoe et al., J. Chem. Soc.Perkin Trans. 1, 590 (1978); Lythgoe, Chem. Soc. Rev. 9, 449 (1983); Tohet al., J. Org. Chem. 48, 1414 (1983); Baggiolini et al., J. Org. Chem.51, 3098 (1986); Sardina et al., J. Org. Chem. 51, 1264 (1986); J. Org.Chem. 51, 1269 (1986); DeLuca et al., U.S. Pat. No. 5,086,191; DeLuca etal., U.S. Pat. No. 5,536,713].

[0031] Hydrindanones of the general structure II are known, or can beprepared by known methods.

[0032] For the preparation of the required phosphine oxides of generalstructure III, a synthetic route has been developed starting from amethyl quinicate derivative which is easily obtained from commercial(1R,3R,4S,5R)-(−)-quinic acid as described by Perlman et al.,Tetrahedron Lett. 32, 7663 (1991) and DeLuca et al., U.S. Pat. No.5,086,191.

[0033] The overall process of the synthesis of compound I is illustratedand described more completely in U.S. Pat. No. 5,843,928 entitled“2-Alkylidene-19-Nor-Vitamin D Compounds” and in application Ser. No.09/878,438 filed Jun. 11, 2001 entitled“1α-Hydroxy-2-Methylene-19-Nor-Homopregnacalciferol and its Uses” thespecifications of which are specifically incorporated herein byreference.

[0034] As used in the description and in the claims, the term“hydroxy-protecting group” signifies any group commonly used for thetemporary protection of hydroxy functions, such as for example,alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafterreferred to simply as “silyl” groups), and alkoxyalkyl groups.Alkoxycarbonyl protecting groups are alkyl-O-CO- groupings such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl or allyloxycarbonyl. The term “acyl” signifies analkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or acarboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl,succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, ora halo, nitro or alkyl substituted benzoyl group. The word “alkyl” asused in the description of the claims, denotes a straight-chain orbranched alkyl radical of 1 to 10 carbons, in all its isomeric forms.Alkoxyalkyl protecting groups are groupings such as methoxymethyl,ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl andtetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl,diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl andanalogous alkylated silyl radicals. The term “aryl” specifies a phenyl-,or an alkyl-, nitro- or halo-substituted phenyl group.

[0035] A “protected hydroxy” group is a hydroxy group derivatised orprotected by any of the above groups commonly used for the temporary orpermanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl,acyl or alkoxycarbonyl groups, as previously defined. The terms“hydroxyalkyl”, “deuteroalkyl”, “aminoalkyl”, “halogenalkyl”,“alkoxyalkyl”, “aryloxyalkyl”, and “fluoroalkyl” refer to an alkylradical substituted by one or more hydroxy, deuterium, amino, halogen,alkoxy, aryloxy, or fluoro group respectively. A “halogen” groupincludes any of the five elements fluorine, chlorine, bromine, iodineand astatine that form a part of group VIIA of the periodic table.

[0036] Referring now to Schemes I-III, there are illustrated threedifferent methods of synthesizing 2MBP starting with vitamin D₂. Thefirst five steps are identical (shown in Scheme I) for each synthesis toobtain the protected 20(S)-aldehyde. Thereafter, in Schemes I and II thealdehyde is converted to a protected 20(S)-alcohol which in turn has itsside chain converted to bis-homo in two different ways (Scheme I versusScheme II). In contrast, Scheme III illustrates a direct conversion ofthe protected 20(S)-aldehyde to the bis-homo side chain.

We claim:
 1. (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferolin crystalline form.
 2. The crystalline form of claim 1 having molecularpacking arrangement defined by orthorhombic space group P2(1)2(1)2(1)and unit cell dimensions a=6.6A°, b=15.5A°, c=20.1A°, α=90°, β=90° andγ=90°.
 3. The three dimensional structure for(20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol as definedby the parameters set forth in claim
 2. 4. A method of purifying(20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol, comprisingthe steps of: (a) boiling a solvent selected from the group consistingof acetone, ethyl acetate, isopropanol, chloroform, dichloromethane anddiethyl ether under inert atmosphere; (b) dissolving a productcontaining (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferolto be purified in said solvent; (c) cooling said solvent and dissolvedproduct below ambient temperature for a sufficient amount of time toform a precipitate of(20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol crystals,and (d) recovering the(20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol crystals. 5.The method of claim 4 including the further step of allowing saidsolvent and dissolved product to cool to ambient temperature prior tocooling below ambient temperature.
 6. The method of claim 4 wherein saidinert atmosphere is an argon atmosphere.
 7. The method of claim 4wherein said solvent and dissolved product is cooled to between about35° F. to about 45° F.
 8. The method of claim 4 wherein the step ofrecovering comprises filtering.
 9. The method of claim 4 including thefurther step (e) comprising repeating steps (a) through (d) using therecovered crystals from step (d) as the product of step (b).